PL179039B1 - Methods of producing intermediate compounds for HIV protease inhibitors and a new PL PL PL indirect compound - Google Patents

Abstract

1. A method of preparing HIV protease inhibitor intermediates of formula I wherein: chiral center a has the S configuration; r is equal to 1; R 1 and R 2 are joined together to form a cyclic structure selected from: R 3 is selected from phenyl and groups of formulae: R 4 is t-butyl, characterized in that a compound of formula IV is reacted: wherein chiral center a has the S configuration; and r and R are as defined above for formula I, with an amine of formula V: wherein R 1 , R 2 and R 4 are as defined above for formula I, in the presence of a solvent, at a temperature from ambient temperature to the boiling point of the solvent. P L 1 7 9 0 3 9 B 1 PL PL PL

Description

The present invention relates to new processes for the preparation of intermediates for HIV protease inhibitors, and to a novel intermediate useful in these methods.

The HIV protease inhibitors described in EP 0541168, in particular the compound L-735,524 and its pharmaceutically acceptable salts, inhibit the action of the protease (proteinase) encoded by the human activity deficiency virus (HIV). Such compounds are of value in the prevention of HIV infection, in the treatment of HIV infection, and in the treatment of acquired immune deficiency syndrome (AIDS).

The retrovirus, designated human immunodeficiency virus (HIV), is the etiological factor of a complex disease involving the gradual progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous systems. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retroviral replication is the extensive post-translational processing (processing) of precursor polyproteins by virionically encoded protease into mature virion proteins necessary for virus organization and functioning. Inhibiting this process prevents the production of a virus normally capable of causing infection. For example, Kohl N.E. et al., Proc. Natl. Acad. Sci., 85, 4686 (1988) showed that genetic inactivation of HIV-encoded protease leads to the production of immature, non-infectious viral particles. These results indicate that inhibition of HIV protease is a viable (current) method of treating AIDS and preventing the occurrence and treatment of HIV-induced infections.

The nucleotide sequence in H1V indicates the presence of the poli gene in one open reading region [Rainer L., Nature, 313, 277 (1985)]. The homology in the amino acid sequence provides evidence that the poi sequence codes for reverse transcriptase, a certain HIV endonuclease and protease [Toh H. et al., EMBO J., 4, 1267 (1985)]; Power M.D. et al., Science, 231, 1567 (1986); Pearl L.H. et al., Nature, 329, 351 (1987)]. The end-product compounds, including the compound described in Example 4 L-735,524 below, which can be obtained from the novel intermediates and process of the invention are HIV protease inhibitors and are disclosed in EPO 541,168 published May 12, 1993.

Previously, the synthesis of L-735,524 and related compounds was carried out in a 12-step procedure in which the hydroxyl-protected dihydro-5 (S) -hydroxymethyl-3 (2H) furanone was alkylated and then the alkylated furanone was substituted with a piperidine moiety leaving the alcohol function. The product of this combination was hydrolyzed to open the furanone ring to the hydroxy acid form and the acid was finally coupled with 2 (R) -hydroxy-1 (S) -aminoindane. Such a procedure is described in EPO 541,168. The extremely long route of this synthesis (12 steps) makes the process very time-consuming and labor-intensive and requires the use of many expensive reagents and expensive starting materials. A route with fewer synthetic steps and using fewer reagents would save time and economic benefits.

A modified synthesis of L-735,524 and related compounds is also shown in EPO 541,168. It is based on the diastereoselective alkylation of an enolate derived from N- (2 (R) -hydroxy-1 (S) -indan-N, O-isopropylidenyl) -3-phenyl-propanamide, in which the C3-C5 three-carbon unit is introduced as a group allyl and then oxidized. The problems encountered in this way are: (a) the introduction of the three-carbon glycidyl moiety requires a four-step synthesis, (b) the process uses a very toxic OSO4, and (c) a low diastereoselectivity is obtained in the dihydroxylation step. Thus, it would be expedient to directly introduce the three-carbon unit in the proper oxidized chiral form into the process.

Moreover, the synthesis of the chiral piperazine intermediate was performed in a 6-step procedure from 2-pyrazinecarboxylic acid and required the use of expensive reagents such as BOC-ON and EDC. It is therefore desirable to develop a shorter route to the piperazine intermediate which does not require the use of expensive reagents.

Several examples of the condensation of stabilized carbonates with glycidol and its derivatives (activated and unactivated) are known in the literature, although none of the

The known methods did not give the new epoxide in good yield; see, e.g., Hanson R.M., Chem. Rev. 1991, 91, 437-475. In the case of activated glycidol derivatives and carbon nucleophiles, this is mainly due to the expected and unfavorable "double" attachment of the nucleophile to the epoxy product.

Moreover, none of the known examples uses an amide moiety as a stabilizing carbanion (amide enolate), and in addition, none of the known examples uses the coupling of a stabilized chiral carbanion to a chiral, non-racemic glycidol derivative (double diastereoselection).

Condensations of stabilized carbanions with activated non-racemic glycidol derivatives have also been described: the malonate anion was condensed with both non-racemic epichlorohydrin and non-racemic glycidyl triflate ii to give cyclopropyl lactone iii. See, e.g., Pirrung M.C. et al., Hevetica Chimica Acta 1989, 72, 1301-1310 and Burgess K. et al., J. Org. Chem. 1992, 57, 5931-5936. Thus, in this case, the intermediate epoxide is further reacted to form a cyclopropyl ring. In case i, the initial reaction with the malonate anion is at the epoxy terminus (C3), while for case ii the initial reaction is at the end of the triflate (C1).

COOR

COOR

ii

A related example is the reaction of a v-derived sulfone-stabilized carbanion with iv glycidyl tosylate to yield vi-hydroxy tosylate. See, e.g., Baldwin J.E., J. Chem. Soc. Chem. Commun. 1992, 1249-1251. Although in this case the double attachment of the carbanion is not the main problem, an additional step is necessary to convert the intermediate hydroxytosylate vi to the expected epoxide vii.

3 1 ę ^^^ OTS iy principle TMS tm ς OTs TMS y 1 b ^b - _{phSQ OH} base vi Th4S ^^ PhSO ₂ ° vii

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Likewise, there are no known examples in the literature, and it is not expected that nitrogen nuclephiles will be able to attach selectively to activated glycidol derivatives in good yields without the problem of double attachment.

It is also known in the art to condense amide enolates derived from N- (2 (R) hydroxy-1 (S) -indan-N, O-isopropylidenyl) -3-phenylpropanamide 1 with alphaamino epoxides viii protected, leading to the expected hydroxyethylene isoster dipeptide intermediates and x with a high degree of stereochemical control at the C2- (R) stereocenter. See, e.g., Askin D. et al., J. Org. Chem., 1992, 57, 2771-2773 and reported by Askin D. et al. U.S. Patent No. 5,169,952. After hydrolysis, deprotected hydroxyethylene isosteric dipeptide inhibitors are obtained.

The separation of 2-piperazinecarboxylic acid from (+) - CSA is known. See, e.g., Felder et al., Helvetica Chimica Acta, 1960, 43, 888. However, examples for the separation of piperazineamides are not known in the literature.

The present invention provides a much more convenient method for the preparation of HIV protease inhibitors than those known previously. It allows a much shorter, more diastereoselective and much more efficient synthesis of the compounds disclosed in EPO 541,168, and especially L-735524, without the need to use toxic reagents such as osmium tetrachloride or such extremely expensive reagents as (S) - (+) - dihydro5 - ( hydroxymethyl) -2 (3H) -furanone.

Summary of the invention

The present invention relates to new methods for the preparation of intermediates of formulas I and IV useful in the synthesis of HIV protease inhibitors, in particular compounds disclosed in EPO Patent 541,168.

The present invention uses new synthetic methods for the preparation of transient epoxides such as 3 which are useful in the synthesis of HIV protease inhibitors. The invention comprises the reaction of an amide enolate, such as the enolate derived from compound 1, with an activated non-racemic glycidol derivative, such as 2 (S) -glycidyl tosylate 2, leading in good yield in one step to an epoxide such as 3. The result of this reaction is unexpected as that epoxide 3 was expected to undergo further reaction under the coupling conditions to give a large amount of the dimeric product 3-a and thus a low yield of 3.

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The invention further includes epoxy intermediates and their conjugation with the amines of formula V defined below to lead to HIV protease intermediates and final products.

Certain abbreviations that may appear in this application mean:

Designation

BOC (Boc)

CBZ (Cbz)

TBS (TBDMS)

Designation

Ts or tosyl or tosylate Ns or nosyl or nosylate Tf or triflyl or triflate Ms or mesyl or mesylate

Designation

BOP reagent

ΒΟΡ-CI

EDC

Designation

BOC-ON (BOC) ₂ O (BOC ₂ O or BOC ₂ O)

Shortcuts

Protective group t-butyloxycarbonyl benzyloxycarbonyl (carbobenzoxy) t-butyl-dimethylsilyl

P-toluenesulfonyl activating group

- nitro benzenesulfonyl and trifluoromethanesulfonyl methanesulfonyl

Benzotriazol-1-yloxytris (dimethylamino) -phosphonium chloride hexaphlorophosphate coupling reagent, bis (2-oxo-3-oxazolidinyl) phosphinium hydrochloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide

Another

2- (tert-butylcarbonyloxyimino) -2-phenylacetonitrile di-t-butyl dicarbonate tetrabutyl ammonium fluoride

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nBuLi (nBuli) n-butyl lithium (S) -CSA (lS) - (+) - 10-camphorsulfonylic acid DIAE or DIPEA diisopropylethylamine DMAP dimethylaminopyridine DME dimethoxyethane DMF dimets 1 ofbrmamid Et ₃ N triethylamine EtOAc ethyl acetate g hour (hours) IPA 2-propanol LDA lithium diisopropylamide L-PGA (L) -pyroglutamic acid TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

According to the invention, a process for the preparation of intermediates for HIV protease inhibitors of formula 1

wherein:

chiral center a has the configuration S;

r equals 1:

0 ^{v J}

R and R are linked together to form a cyclic structure selected from:

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R ³ is selected from a phenyl group and groups of formulas:

R ⁴ is a t-butyl group, in which a compound of formula IV is reacted:

IV wherein the chiral center a has the configuration S;

and R ³ are as defined above for formula I, with the amine of formula V:

R ²

wherein R ¹ , R ² and R ⁴ are as defined above for formula I, in the presence of the solvent, at a temperature from ambient temperature to the boiling point of the solvent.

Preferably the reaction is carried out in a solvent selected from C1-3 alcohols, particularly preferably methanol.

In one preferred embodiment, the reaction is carried out in isopropanol at a temperature of 83 ° C to 85 ° C.

The starting compound for the preparation of the compounds of formula I, i.e. the compound of formula IV, is a novel compound. Preferably, in the process according to the invention for the preparation of compounds of formula I, a compound of formula IV is used, prepared by reacting an amide of formula III:

R ^3_ (CH ₂ ) r

o wherein the chiral center a has the configuration S; and r and R are as defined above, in the presence of a strong base at low temperature, with:

a) a compound of formula II:

179 039 wherein the chiral center a has the S configuration and X is hydrogen, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl or 3-nitrobenzenesulfonyl or with b) epichlorohydrin of the formula:

Compound II is preferably used in which X is para-toluenesulfonyl.

In a preferred embodiment of the compounds of formula I, R ³ is phenyl and R, ^L and R ² together form a structure of the formula:

The invention therefore also relates to a process for the preparation of intermediates for HIV protease inhibitors of formula IV

wherein:

chiral center a has the configuration S;

r is equal to 1;

R ³ is selected from a phenyl group and groups of formulas:

consisting in reacting an amide of formula III:

179 039 wherein r and R ³ are as defined above, in the presence of a strong base at low temperature, optionally in the presence of a solvent, with:

a) a compound of formula II:

in which the chiral center a has the S configuration and X is hydrogen, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl or 3-nitrobenzenesulfonyl or with b) epichlorohydrin of the formula

Preferably a strong base is used selected from the group consisting of the following: LiN [(CH ₃ ) ₃ Si] ₂ , KN [(CH ₃ ) ₃ Si] ₂ , NaN [(CH ₃ ) ₃ Si] ₂ , n-butyl lithium, s -butyllithium, t-butyllithium, potassium t-butoxide, lithium diisopropylamide, lithium isopropylcyclohexylamide, lithium pyrrolidide, lithium tetramethylpiperidide, phenyl lithium, isopropylmagnesium chloride and isobutylmagnesium chloride. In such a case, the reaction is preferably carried out at a temperature from -82 ° C to 0 ° C. Also, preferably in such a case, the reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and t-butyl methyl ether, or a mixture thereof.

A strong base selected from the group consisting of n-butyl lithium, s-butyl lithium, LiN [(CH ₃ ) ₃ Si] ₂ and lithium diisopropylamide is particularly preferably used. In such a case, it is preferred that the metallation reaction of amide III is carried out at a temperature of -82 ° C to -40 ° C, and the reaction of the metallated derivative III with the compound of formula II is carried out at a temperature of -50 ° C to -10 ° C. Preferably, tetrahydrofuran is used as the solvent.

In another preferred embodiment, a strong base selected from the group consisting of n-butyl lithium and LiN [(CH ₃ ) ₃ Si] _{2 is used} . In such a case, it is preferred that the metallation reaction of amide III is carried out at a temperature of -50 ° C to -45 ° C, and the reaction of the metallated derivative III with the compound of formula II is carried out at a temperature of -30 ° C to -20 ° C.

Preferably in the compounds of formula IV, R ³ is a phenyl group.

The invention also relates to a novel intermediate for the production of HIV protease inhibitors, represented by the formula:

Scheme 1 below is an illustration of the invention. In no way are the methods of the invention limited by any particular substituents shown in the scheme which is merely illustrative.

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Intermediates of formula IV are obtained by reacting glycidol or its derivatives II with amide III in the presence of a strong base. A metal base must be a strong rule; it may or may not be used in an inert anhydrous organic solvent such as e.g. cyclic or acyclic hydrocarbons including hexane, pentane, cyclohexane etc. Suitable strong bases are: LiN [(CH ₃ ) ₃ Si] 2, KN [( CH ₃ ) ₃ Si] 2, NaN [(CH ₃ ) ₃ Si] 2, n-butyl lithium, (n-BuLi), s-BuLi, t-BuLi, potassium t-butoxide, lithium diisopropylamide (LDA), lithium isopropyl cyclohexylamide , lithium pyrrolidide, lithium tetramethylpiperidide, phenyl lithium, isopropylmagnesium chloride, isobutylmagnesium chloride and other similar strong bases known in the art. Preferred strong bases are n-BuLi, s-BuLi, LiN [(CH ₃ ) ₃ Si] 2, and LDA; of these, LiN [(CH ₃ ) ₃ Si] 2 and LDA are most preferred.

It is preferred to use about 1 to 2 mole equivalents of strong base per 1 mole equivalent of III, most preferably the ratio of mole equivalents of base to mole equivalents of III is about 1.15: 1. The reaction of compounds II and III can be carried out by combining II and III in one pot and then adding a strong base or it can be carried out sequentially, i.e. by first treating amine III with a base and then adding II. A strong base metalates amide III alpha to the carbonyl group and produces a reactive amide metalloenolate which opens the epoxide II ring at the terminal position to form product IV. In the isosteric product IV, a new asymmetry center is generated in position 2.

It is preferable to carry out the reaction at low temperature, for example in a range between about -82 ° C to 0 ° C. To effect amide III metalation it is more preferred to maintain the temperature between about -82 ° C and -40 ° C, preferably between about -50 ° C and -45 ° C. The reaction temperature of the metallated amide with compound II to yield product IV is maintained between about -50 ° C and -10 ° C, most preferably between about -30 ° C and -20 ° C for 4-5 hours.

It is recommended to carry out the reactions I with III in an ether type solvent. Ether type solvents are any suitable solvent for carrying out this type of reaction.

E.g., tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and t-butyl methyl ether, and combinations thereof, with tetrahydrofuran being preferred.

Compounds of formula I are prepared by reacting a compound of formula IV with an amine of formula V. It is preferable to use about 1 to 3 molar equivalents of amine V per 1 molar equivalent of epoxide IV; it is most preferred to maintain a ratio of 1.05: 1 molar V: IV equivalents.

The reaction may be carried out in any suitable solvent, for example selected from hydrocarbons like toluene, ethers like diethyl ether, alcohols like methanol, ethanol and isopropanol, nitriles like acetonitrile and esters like ethyl acetate or mixtures thereof; preferably the use of alcohols, most preferably isopropanol. The reaction temperature is controlled at ambient temperature to the boiling point of the solvent used; it is preferable to carry out the reaction at elevated temperature, e.g. in the range of 80-90 ° C, preferably between about 83 ° C and 85 ° C.

Activated glycidols of formula II can be obtained by methods known in the art as described, for example, in J. Klauder et al., J. Org. Chem., 1989, 54, 1295-1304, and references cited therein.

The amide compounds of formula III are obtained by standard methods known to those skilled in the art such as, for example, the procedure described in example 1, starting from the appropriate starting materials.

In the practice of the present invention, protective groups such as nitrogen protecting groups are used where appropriate. For example, the nitrogen at the 4-position of piperazine 2-t-butylcarboxamide can be blocked with BOC, CBZ, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, trifluoroacetamide, trialkylsilyl, or other protecting groups known in the art.

End products - HIV protease inhibitors are obtained from compounds of formula I by removing any remaining protective groups present in the molecule by deprotection methods well known to those skilled in the art. For example, the ketal protecting group can be removed by treating I with acid in the presence of methanol or an aqueous acid solution, or e.g. with 1 N HCl in THF, leading to the end products HIV protease inhibitors. Compounds of formula I can also be further substituted by methods known in the art.

Preferred compounds of formula I which are obtained by the process of the invention are the compounds of formulas I-a and I-b

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Compound I-b can be obtained by direct coupling of 2 (S) -t-butylcarboxamide-4-N- (methyl-3-pyridyl) -piperazine with IV-a. It is preferred to obtain the final product L-735,524 by deprotecting and "picolylating" (reaction with picoline) of I-a as illustrated in Examples 3-4.

The production methods and intermediates of the present invention are useful in the preparation of end products useful in inhibiting HIV protease, preventing and treating human deficiency virus (HIV) infection, and treating consequent pathological conditions such as AIDS. Treatment of AIDS or the prevention and treatment of HIV infection is defined, but not limited to, the treatment of a wide range of conditions associated with HIV infection: AIDS, ARO (AIDS related complex), with or without symptoms, current or potential contagion become HIV. For example, the final compounds obtainable according to the production methods and intermediates of the present invention are useful for use where HIV infection has been suspected, e.g. contact with the patient's blood during surgery.

HIV protease inhibitor end products are also useful in preparing and conducting screening assays for antiviral activity of compounds. For example, end-product compounds are useful in isolating enzyme mutants as an excellent screening tool to find even more potent antiviral compounds. Moreover, such compounds are useful in establishing or determining the binding sites of other antiviral substances to HIV protease, e.g., in competitive inhibition experiments. Thus, the end-product compounds that are obtained according to the production methods and intermediates of the present invention are commercial products for sale for specific purposes.

HIV protease inhibitor compounds which can be obtained from intermediates and according to the production methods of the present invention are disclosed in EPO 541,164. HIV protease inhibitor compounds are administered to patients in need of such treatment in the form of pharmaceutical compositions consisting of a pharmaceutical carrier and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof. EPO 541,164 discloses suitable pharmaceutical forms, routes of administration, salt forms and dosages for these compounds.

The invention is illustrated by the following representative examples of its implementation.

These procedures are exemplary only and should not be construed as limiting the novel process of the invention.

Example I. Preparation of the amide 1.

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A solution of (-) - cis-1-aminoindan-2-ol (884 g, 5.93 mol) in 17.8 L of dry THF (KF = 55 mg / ml) (KF means Karl Fisher method for determining the amount of water) and triethylamine (886 mL, 6.22 moles) in a 50 L round bottom flask equipped with a thermocouple, mechanical stirrer and nitrogen inlet with bubbler is cooled to 15 ° C. 3-Phenylpropionyl chloride (1000 g, 5.93 mol) is then added over a period of 75 minutes while maintaining the internal temperature of the mixture between 14-24 ° C with an ice-water bath. After the addition, the mixture is kept at 18 to 20 ° C for 30 minutes, checking the disappearance of (-) - cis-1-aminoindan-2-ol by HPLC.

The progress of the reaction is followed by high resolution liquid chromatography (HPLC): 25 cm Dupont C8-RX column, 60:40 acetonitrile / 10 mM (KH2PO4 / K2HPO4), 10.0 ml / min, sample injection volume = 20 ml , detection = 200 nm, sample preparation = 500 x dilution. Approximate retention times:

retention time (min) identification

6.3 cis-aminoindanol

The reaction is treated with pyridine p-toluenesulfonate (241 g, 0.96 mol, 0.16 eq) and stirred for 10 minutes (the pH of the mixture after diluting 1 ml of the sample with the same amount of water is 4.3-4.6). Then 2-methoxypropene (1.27 L, 13.24 mol, 2.2 eq.) Is added and the reaction mixture is heated to 38-40 ° C for 2 hours. The mixture is cooled to 20 ° C and partitioned with ethyl acetate (12 L) and 5% aqueous NaHCO3 solution (10 L). The mixture precipitates and the layers are separated. The ethyl acetate extract is washed with 5% aqueous NaHCO 3 (10 L) and water (4 L). The ethyl acetate extract is dried by distillation at ambient pressure and the solvent is changed to cyclohexane (total volume ~ 30 L). After completion of distillation and concentration (20% by volume of the ethyl acetate extract), the hot cyclohexane solution was allowed to cool slowly to 25 ° C to crystallize the product. The obtained sludge is cooled further to 10 ° C and left for 1 hour for maturation. The product is isolated by filtration and the wet cake is rinsed with cold (10 ° C) cyclohexane (2 x 800 ml). The washed wet cake is dried under vacuum (65 cm Hg) at 40 ° C to afford 1.65 kg of acetonide 1 (86.4%, 98 area% by HPLC.

Ή NMR (300.13 MHz, CDCl ₃ , major rotamer) δ 7.36-7.14 (m, 9H), 5.03 (d, J = 4.4 1, 1H), 4.66 (m, 1H), 3.15 (m, 2H), 3.06 (br s, 2H), 2.97 (m, 2H), 1.62 (s, 3H), 1.37 (s, 3H);

¹³ CNMR (75.5 MHz, _{CDC1 3} , main rotamer) δ _ε 168.8, 140.9, 140.8, 140.6, 128.6, 128.5, 128.4, 127.1, 126, 3, 125.8, 124.1, 96.5, 78.6, 65.9, 38.4, 36.2, 31.9, 26.5, 24.1.

Analysis calculated for C21H23NO2:

Calculated: C 78.47; H7.21; N 4.36.

Found: C 78.65; H 7.24; N 4.40.

Example II. Epoxy production 3.

a. p-Toluenesulfonyl method

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A solution of acetonide 1 (1000 g, 3.11 mol) and glycidyl 2 (S) -p-toluenesulfonylate 2 (853 g, 3.74 mol, 1.2 eq.) In 15.6 L THF (KF = 22 mg / ml ) in a 50 L 4 necked round bottom flask equipped with a thermocouple, mechanical stirrer, feeding funnel and nitrogen inlet, degassed 3 times by alternating nitrogen purge and vacuum generation and cooled to -56 ° C. Lithium hexamethyldisilizide, LiN [(CH3) 381) 2 (2.6 L, 1.38 M, 1.15 equiv) is then added over a period of 2 hours maintaining the internal temperature between -50 and -40 ° C. The mixture is stirred at -45 to -40 ° C for 1 hour and then allowed to warm to -25 ° C over a period of 1 hour. The mixture is then stirred for 4 hours at -25 to -22 ° C (or until the starting acetonide is 3% area).

Reaction progress is followed by HPLC: 25cm x 4.6nm, Zorbax Silica column, 20% ethyl acetate in hexane, 2.0ml / min, sample injection volume = 20ml, detection = 254nm, sample preparation = 100 x dilution . Approximate retention times:

retention time (min) identification

5.5 amide 1

6.5 glycidyl p-toluenesulfonylate 2

13.5 epoxy 3

The reaction mixture was quenched with deionized water (6.7 L) at -15 ° C and partitioned with ethyl acetate (10 L). The mixture is shaken and the layers are separated. The ethyl acetate extract is washed with a mixture of 1% aqueous NaHCOL (5 L) and saturated NaCl (0.5 L). The ethyl acetate extract (28.3 L) is concentrated by distillation in vacuo (70 cm Hg) and further ethyl acetate is added to completely replace the solvent with ethyl acetate (final volume = 11.7 L). The concentrated ethyl acetate solution is then re-solvent exchanged with MeOH to crystallize the product and concentrated to a final volume of 3.2L. The residual ethyl acetate is removed by charging 10L methanol and collecting 10L distillate. The obtained sludge is stirred at 22 ° C for 1 hour, then cooled to 5 ° C and matured for 0.5 hour. The product is isolated by filtration and the wet cake is rinsed with cold methanol (2 x 250 ml). The washed cake is dried under vacuum (65 cm Hg) at 25 ° C to afford 727 g of epoxide 3 (61.2%, 98.7% major epoxide area by HPLC.

¹³ CNMR (300 MHz, CDCl3: 171.1, 140.6, 140.5, 139.6, 129.6, 128.8, 128.2, 127.2, 126.8, 125.6, 124, 1, 96.8, 79.2, 65.8, 50.0, 48.0.44.8, 39.2, 37.4, 36.2, 26.6, 24.1.

b. Epichlorohydrin method

Preparation of epoxy 3 (epichlorohydrin method)

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A solution of acetonide 1 (3.00 g, 9.33 mmol) in 47 ml of sieve dried THF is degassed with nitrogen, then the resulting solution is cooled to -78 ° C and treated with 8.0 ml of lithium hexamethyldisilazide solution (1.38 M in THF). The resulting solution is allowed to age at -78 ° C for 15 min, then 2 (S) -epichlorohydrin (1.2 ml, 15.3 mmol) is added dropwise and the resulting mixture is allowed to warm to -25 ° C. for 1 hour and allowed to mature for 1 hour. The reaction mixture is cooled back to -78 ° C and treated with 3.0 ml of lithium hexamethyldisilylazide solution followed by 1.0 ml of (S) -epichlorohydrin. The reaction mixture is allowed to warm to -25 ° C and mature for 2 hours. The reaction mixture was quenched with 20 mL of saturated aqueous sodium bicarbonate solution and extracted with 120 mL of EtOAc, then again with 60 mL of EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give 3.97 g of an oil which was purified by silica gel chromatography (80 g SiO ₂ , eluting with 4: 1 hexane / ethyl acetate) to give 2.9 g of a mixture of the desired epoxide 3 and a chlorohydrin intermediate. Part of the mixture (1.29 g) was dissolved in sieve dried THF (20 ml) at 25 ° C, treated with 1.73 g of a 25 wt% potassium t-amylate solution and allowed to mature at 25 ° C for 1 hour. The reaction mixture is partitioned between ethyl acetate and saturated potassium bicarbonate, and the layers are separated. The organic phase is washed with brine, dried (MgSO4) and concentrated under reduced pressure to an oil. The oil was purified by silica gel chromatography (80 g SiO ₂ , eluting with 4: 1 hexane / ethyl acetate) to give 1.1 g (70% of total) epoxide 3.

Example III. Compound production 6.

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Sludge of 2 (S) -butylcarboxamido-4-N-Boc-piperazine 4 (1950 g, 6.83 mol,> 99.5% ee) (ee is enantiomeric excess) and epoxide 3 (2456 g, 97.5 mixture: 2.5 4S / R epoxides, 6.51 mol) in isopropanol (2-propanol, 18.6 L) in a 72 L four inlet round bottom flask equipped with a mechanical stirrer, reflux condenser, steam bath, Teflon coated thermocouple and nitrogen inlet , is heated to reflux (internal temperature 84-85 ° C) under reflux. After 40 minutes, a homogeneous solution is obtained. The mixture was heated to reflux for 28 hours.

The internal temperature was 84-85 ° C during reflux. The reaction progress is followed by HPLC: 25 cm Dupont C8-RX column, 60:40 acetonitrile / 10 mM (KH2PO4 / K2HPO4), 1.0 ml / min, detection = 220 nm, sample preparation = 2 μΐ, reaction mixture diluted to 1 ml in acetonitrile. Approximate retention times:

retention time (min) identification

4.8 piperazine 4

8.9 epoxy 3

15.2 Conjugate Product 5

After 28 hours, the remaining epoxide 3 and coupled product 5 (HPLC analysis) were 1.5 area% and 91-93 area%, respectively. The mixture is cooled to 0-5 ° C and 20.9 L of 6N HCl are added keeping the temperature below 15 ° C. After the addition, the mixture is warmed to 22 ° C. You can notice gas evolution (isobutylene). The mixture is aged at 20 to 22 ° C for 6 hours.

The progress of the reaction is followed by HPLC, conditions identical to the above. Approximate retention times:

retention time (min) identification

7.0 cis-aminoindanol

11.9 compound 6

15.1 Conjugate product 5

The mixture is cooled to 0 ° C and 7.5 L of 50% NaOH is added slowly until the pH of the mixture is adjusted to 11.6, keeping the temperature below 25 ° C during the addition. The mixture was partitioned between ethyl acetate (40 L) and water (3 L). Shake off and separate the layers. The organic phase (60 L) was concentrated under reduced pressure (73 cm Hg) and the solvent exchanged with DMF then concentrated to a final volume of 10.5 L (KF = 1.8 mg / ml). The yield of compound 6 in ethyl acetate according to the HPLC test is 86.5%. Compound 6 in DMF is used directly in the next step without further purification. For insulated 6:

¹³ CNMR (75.4 MHz, CDC1 ₃₎ δ 175.2, 170.5, 140.8, 140.5, 139.9, 128.5, 127.9, 126.8, 126.5, 125, 2, 124.2, 73.0, 66.0, 64.8, 62.2, 57.5.49.5.47.9, 46.4, 45.3, 39.6, 39.3, 38.2, 28.9.

Example IV. Preparation of L-735524-monohydrate.

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A solution of 6 in DMF (10.5, 1, KF = 10 mg / ml) from the previous step is charged with 8 l of sieve-dried DMF (KF <30 mg / l) and the mixture is heated on a steam bath under reduced pressure of 75 cm. Hg to distill mainly water and / or residual isopropanol or ethyl acetate. The final volume of the concentrated solution is 13.5 L (KF = 1.8 mg / mL), then triethylamine (2.86 L, 20.51 mol) is added to the solution at 25 ° C, followed by picolyl chloride hydrochloride (96 %, 1287 g, 7.84 mol). The obtained sludge is heated to 68 ° C.

The progress of the reaction is followed by HPLC under identical conditions to the previous step. Approximate retention times:

retention time (min) identification

2.7 DMF

4.2 3-picolyl chloride

4.8 L-735524

15.2 compound 6

The mixture is allowed to age at 68 ° C until the residue of compound 6 is less than 0.3 area% by HPLC analysis. The mixture is stirred at 68 ° C for 4 hours then cooled to 25 ° C and partitioned between ethyl acetate (80 L) and a mixture of 24 L saturated aqueous NaHCO 3 and distilled water (14 L). The mixture is shaken at 55 ° C and the layers are separated. The ethyl acetate layer is washed three times with water (20 L) at 55 ° C. The washed ethyl acetate layer is concentrated at atmospheric pressure to a final volume of 30 1. At the end of the atmospheric distillation, water (560 ml) is added to the hot solution, the mixture is cooled to 55 ° C and seeded with L-735524 monohydrate. The mixture is cooled to 4 ° C and filtered to collect the product. The product was rinsed with cold ethyl acetate (2 x 3 L) and dried under the house-equipped vacuum at 25 ° C to afford 2905 g (70.7%) of L-735524 monohydrate as a white solid.

Example 5 Pyrazine-2-tert-butyl carboxamide 9.

CONHt-Bu

2-piperazinecarboxylic acid (8) Oxalyl chloride

Tert-butylamine (KF = 460 pg / ml)

EtOAc (KF = 56pg / ml)

DMF

3.35 kg (27 moles)

3.46 kg (27.2 mol)

9.36 1 (89 moles)

271

120 ml

1-propanol 30 1

Suspend carboxylic acid (8) in 27 L of EtOAc and 120 mL of DMF in a 72 L 3 necked flask with mechanical stirring under nitrogen and cool to 2 ° C. Oxalyl chloride is added keeping the temperature between 5 and 8 ° C.

The addition is complete in 5 hours. During the exothermic addition, CO and CO 2 are released. The HCl produced remains mainly in solution. A precipitate is observed which is probably the HCl salt of the acid pyrazine chloride. The acid chloride formation test is carried out by quenching the anhydrous reaction sample with t-butylamine. <0.7% of acid 8 remains at the end of the reaction.

The acid chloride formation termination test is important as incomplete reaction leads to the formation of the bis-tert-butyl oxamide as an impurity.

The reaction can be followed by HPLC: 25 cm Dupont Zorbax RXC8 column with a flow rate of 1 ml / min. and detection at 250 nm; linear gradient from 98% 0.1% aqueous H3PO4 and 2%

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CH3CN, up to 50% aqueous H3PO4 and 50% CH3CN at 30 min. Retention times: acid 8 = 10.7 min., Amide 9 = 28.1 min.

The reaction mixture is allowed to age for 1 hour at 5 ° C. The resulting slurry is cooled to 0 ° C and add tert-butylamine at such a rate as to keep the internal temperature below 20 ° C. The addition takes 6 hours as the reaction is very exothermic. A small portion of the tert-butylammonium hydrochloride produced is removed from the reaction mixture as a fluffy solid.

The mixture is allowed to age at 18 ° C for an additional 30 minutes. Precipitated ammonium salts are removed by filtration. The filtered cake is rinsed with EtOAc. The combined organic phases are washed with 6 L ₃ % NaHCO 3 and 2 x 2 L saturated aqueous NaCl. The organic phase is treated with 200 g Darco G60 carbon, filtered through Solka Fiok and the cake is rinsed with 4 L EtOAc.

Coal treatment effectively eliminates the slightly purple color in the product.

The EtOAc solution of 9 is concentrated at 10 mbar to 25% of its original volume. 11-propanol is added and distillation continued until a final volume of 20 L is reached.

At this point, the EtOAc content is below the detection level ^! HNMR (<1%). The internal temperature is kept below 30 ° C during the solvent changeover. The solution of compound 3 in 1-propanol / EtOAc is stable at reflux at atmospheric pressure for several days.

Evaporation of the sample gives a brown solid, mp. 87-88 ° C.

¹³ C NMR (75 MHz, CDCl ₃ , ppm) 161.8, 146.8, 145.0, 143.8, 142.1, 51.0, 28.5.

Example VI. rac-2-tert-butyl carboxamide-piperazine 10.

H2 / Pd (OH) ₂

N CONHt-Bu 9

Materials

A solution of pyrazine-2-tert-butyl carboxamide 9 (2.4 kg, 13.4 mol) in 1-propanol, 12 120% Pd (OH) ₂ / C 16% by weight. water 144 g.

The 9/1-propanol pyrazine-2-tert-butyl carboxamide solution is placed in a 5 gallon autoclave. The catalyst is added and the mixture is hydrogenated at 65 ° C under 40 psi (3 atm) H ₂ .

After 24 hours, the reaction uses theoretical amount of hydrogen and GC analysis shows <1% of compound 9. The mixture is cooled, purged with N ₂ and the catalyst is removed by filtration through Solka Flock. The catalyst is rinsed with 2 liters of warm 1-propanol. It has been found that the use of warm 1-propanol to wash the filtered cake improves filtration and reduces product loss in the cake.

The reaction is followed on a GC: 30m Megabore column, from 100 ° C to 160 ° C at 10 ° C / min, stop for 5 minutes, then at 10 ° C / min. to 250 ° C, retention times: 9 = 7.0 min., 10 = 9.4 min. The reaction can also be monitored by TLC using EtOAc / MeOH (50:50) as solvent and ninhydrin as developer.

Evaporation of the sample indicates that the yield during the amidation and hydrogenation is 88% and that the concentration is 133 g / L.

Evaporation of the sample gives 10 as a white solid, mp. 150-151 ° C.

¹³ C NMR (75 MHz, D ₂ O, ppm) 173.5, 59.8, 52.0, 48.7.45.0, 44.8, 28.7.

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Example VII. piperazine.

Bis (S) -camhorsulfone salt (S) -2-tert-butyl carboxamide-

(+) - CSA

CONHt-Bu \ · 2 (+) - CSA ^ CONHt-Bu

Materials rac-2-tert-butyl carboxamide-piperazine 10 4.10 kg (22.12 mol) in a solution of 1-propanol in 25.5 kg of solvent (S) - (+) - 10-camphorsulfonic acid 10.0 kg ( 43.2 moles)

1-propanol12 1 acetonitrile 391 water 2.41

A solution of the amine 10 in 1-propanol is charged to a 100 L flask with an attached concentrator. The solution is concentrated under 10 mbar (10 ⁴ Pa) and a temperature <25 ° C to about 121.

At this point the product precipitates out of solution, but when the mixture is heated to 50 ° C it dissolves again.

Analysis of a homogeneous sample indicates that the concentration is 341 g / L. The concentration is determined by HPLC: 25 cm Dupont Zorbax RXC8 column with a flow rate of 1.5 ml / min. and detection at 210 nm; isocratic (98/2) CH3CN / 0.1% aqueous H3PO4. Compound 10 retention time: 2.5 minutes. Add acetonitrile (39 L) and water (2.4 L) to give a clear, slightly brown solution.

Determining the amount of water KF titration, and the ratio CH3CN / I-propanol by integrating the H NMR shows that the ratio of the CH3CN / l-propanol / H ₂ O is 26/8 / 1.6. The concentration in the solution is 72.2 g / L.

(S) -1O-camphorsulfonic acid is charged in 4 portions for 30 minutes at 20 ° C. The temperature rises to 40 ° C with the addition of CSA. After a few minutes, a thick white precipitate forms. The white slurry is heated to 76 ° C until all solids are dissolved, the light brown solution is then allowed to cool to 21 ° C for 8 hours.

The product precipitates at 62 ° C. The product is filtered at 21 ° C without maturation and the filtered cake is washed with 5 L of a mixture of CH 3 CN / 1-propanol / H ₂ O 26/8 / 1.6. They are dried at 35 ° C in a vacuum oven under N ₂ , giving 5.6 kg (39%) of compound 11 as a white, crystalline solid, mp 288-290 ° C (with decomposition), [α] β ²⁵ = 18.9 ° (c = 0.37, H ₂ O).

¹³ CNMR (75 MHz, D ₂ O, ppm) 222.0, 164.0, 59.3, 54.9, 53.3, 49.0, 48.1, 43.6, 43.5, 43, 1.40, 6.40.4, 28.5, 27.2, 25.4, 19.9, 19.8.

The ee of the material is 95% according to the following HPLC chiral test: Sample 11 (33 mg) is suspended in 4 ml of EtOH and 1 ml of EtsN. Boc ₂ O (11 mg) was added and the reaction mixture was allowed to age for 1 hour. The solvent is removed completely in vacuo and the residue is dissolved in ca. 1 ml of EtOAc then filtered through a Pasteur pipette filled with SiO ₂ using EtOAc as eluent. Evaporated product fractions are redissolved in hexanes to a concentration of approximately 1 mg / ml. The enantiomers are separated on a Daicel Chiracell AS column with a solvent mixture of hexane / IPA (97: 3) at a flow rate of 1 ml / min. and detection at 228 nm. Retention times: form S = 7.4 minutes, R = 9.7 minutes.

179 039

Example VIII. (S) -2-tert-butylcarboxamido-4-tert-butoxycarbonyl-piperazine4 from salt 11.

H% 2W-CSA _{(Boc) 2} sts

Boc N.

N CONHt-Bu

H.

N CONHt-Bu H 4

Materials

Bis (S) - (+) - CSA salt of (S) -2-tert-butyl carboxamidopiperazine 11, 95% ee 5.54 kg (8.53 mol)

Di-tert-butyl bicarbonate

Et ₃ N

EtOH Punctilious attempts 200

EtOAc

1.86 kg (8.53 mol) 5.95 L (42.6 mol) 55 L

EtOH is added to (S) -CSA 11 salt in a 100 L 3 necked flask with dispenser under nitrogen atmosphere at 25 ° C, followed by EtOH followed by triethylamine. The solid dissolves readily upon addition of Et ₃ N. Dissolve Boc ₂ O in EtOAc and load into the dispenser. A solution of Boc ₂ O in EtOAc is added at such a rate as to keep the reaction temperature below 25 ° C. It takes 3 hours to add. The reaction mixture matured for 1 hour after the addition of the Boc ₂ O solution was complete.

The course of the reaction can be followed by HPLC: 25 cm Dupont Zorbax RXC8 column, flow 1 ml / min. and detection at 228 nm, isocratic (50/50) CH ₃ CN / 0.1 M KH ₂ PO ₄ pH = 6.8 adjusted with NaOH. Compound 4 retention time: 7.2 min. The chirality test is carried out using the same system as in the previous step. The reaction can also be followed by TLC using 100% EtOAc as the solvent. (Rf = 0.7).

The solution was then concentrated to approx. 101 at an internal temperature of <20 ° C in a batch-type concentrator under 10 mbar (10 ⁴ Pa). The solvent exchange was completed by slowly introducing 20 L EtOAc and re-concentrating to ca. 101. The reaction mixture was washed into a separating funnel with 60 L EtOAc. The organic phase is washed with 16 L of 5% aqueous Na2CO3 solution, 2 x 10 L of deionized water and 2 x 6 L of saturated aqueous sodium chloride solution. The combined aqueous phases are back-extracted with 20 L of EtOAc and the organic phase is washed with 2 x 3 L of water and 2 x 4 L of saturated aqueous sodium chloride solution. The combined EtOAc extracts are concentrated at 10 mbar (10 ⁴ Pa) with an internal temperature <20 ° C in a batch concentrator to about 8 1. The cyclohexane solvent is replaced by slowly pouring about 20 L of cyclohexane and re-concentration to ca. 1. 5 L of cyclohexane and 280 mL of EtOAc are added to the sludge and the mixture is heated to reflux, whereupon it goes into solution. The solution is cooled and seeded (10 g) at 58 ° C. The sludge is cooled to 22 ° C in 4 hours and the product is isolated by filtration after 1 hour of maturation at 22 ° C. The filter cake is rinsed with 1.8 L of cyclohexane and dried in a vacuum oven at 35 ° C under nitrogen to afford 1.87 kg (77%,> 99.9% HPLC area, R-isomer below detection level) of Compound 4 in as a light brown powder. [α] D ²⁵ = 22 ° (c = 0.20, MeOH), mp 107 ° C.

¹³ C NMR (75 MHz, CDCl ₃ , ppm) 170.1, 154.5, 79.8, 58.7, 50.6, 46.6, 43.6.43.4, 28.6, 28, 3.

Example IX. Bis salt of (S) -2-tert-butyl-carboxamide-piperazine with (L) pyroglutamic acid.

H.

N ^ 2 L-PGA

H.

N. -2 L-PGA

N CONHt-Bu H

N CONHt-Bu H

179 039

Materials rac-2-tert-butyl carboxamide-piperazine 10 (0.11 mol) in 1-propanol solution 115 ml, total - 21.1 g L-pyroglutamic acid 28 g (0.21 mol) water 5 ml

Charge the solution of rac-2-tert-butyl carboxamide-piperazine 10 in 1-propanol to a 500 mL round bottom flask with reflux condenser, mechanical stirrer and nitrogen inlet. Water is added along with L-pyroglutamic acid and the obtained sludge is boiled. The homogeneous yellow solution is cooled to 50 ° C and seeded with R-amine bis- (L) PGA salt (50 mg). A solid begins to precipitate immediately. The solution is cooled further to 25 ° C and allowed to age for 16 hours. The solid is filtered off at 22 ° C and the filter cake is washed with 35 ml of cold 1-propanol / 1% water mixture. The filter cake is dried at 35 ° C in a vacuum oven with a slow flow of nitrogen to give 23.74 g (48%) of the bis (R) -2-tert-butyl-carboxamide-piperazine salt with (L) pyroglutamic acid. The ee value of the material is 98% according to the HPLC chirality test previously described. The yellow filter liquid contains 22.6 g (46%) of (S) -2-tert-butylcarboxamide-piperazine bis salt of (L) -pyroglutamic acid 12, which has an ee of 95% by HPLC chirality. The filter liquid is evaporated and used directly in the shielding step.

Example X. (S) -2-tert-butyl-carboxamido-4-tert-butoxycarbonyl-piperazine4 from bis salt of (S) -2-tert-butyl carboxamido-piperazine with (L) -pyroglutamic acid 12.

• 2L-PGA

CONHt-Bu (Boc) ₂ O

Materials

(S) -2-tert-butyl-carboxamide-piperazine bis-salt with (L) -pyroglutamic acid, 95% ee 22.6 g (50.1 mmol)

Di-tert-butyl bicarbonate 11.1 g (50.1 mmol)

Et ₃ N 33.5 mL (0.254 mmol)

1-propanol 226 ml

EtOAc 24 ml

To (S) -2-tert-butyl-carboxamido-piperazine bis salt of (L) -pyroglutamic acid in a 500 mL 3 necked flask with dispenser, 1-propanol is added under nitrogen atmosphere. The gummy yellow solid dissolves readily with the addition of Et _{3 N. A solution of Boc 2} O in EtOAc is added for 2 hours at 22 ° C. The reaction mixture matured for 1 hour after the addition was complete.

The reaction can be followed by HPLC and TLC, using the same procedures as for the conversion of 11 to 4.

The solution is then concentrated and the solvent replaced with ethyl acetate (200 mL). The reaction mixture is washed with 50 ml of a 7% aqueous Na ₂ CO _{3 solution} , 2 x 30 ml of water, dried (Na ₂ CO 4) and filtered. The EtOAc solution was concentrated and the solvent replaced with cyclohexane (60 mL). EtOAc (1 mL) was added and the mixture was heated to reflux to dissolve all solids. The mixture is cooled and seeded (50 mg) at 52 ° C. The slurry is cooled to 22 ° C for 2 hours and the product is isolated by filtration after 1 hour of maturation at 22 ° C. The filter cake is rinsed with 8 ml of cyclohexane and dried in a vacuum oven at 35 ° C with a slow flow of N ₂ to give 10.8 g (74%) (> 99.9 area% by HPLC, R isomer below detection level) of compound 4 in the form of an off-white powder.

179 039

Example XI. Kinetic conversion of (S / R) -2-tert-butylcarboxamido-4-tert-butoxycarbonyl-piperazine 13 into 4.

Boc

N CONHt-Bu H

CONHt-Bu

Materials

Crude (S / R) -2-tert-butyl-carboxamido-4-tert-butoxycarbonylpiperazine 13 1.40 g of (S) -2-tert-butylcarboxamido-4-tert-butoxycarbonylpiperazine 4 (> 99.5% ee) 4x0 , 14g

Methylcyclohexane with 2% v / v EtOAc 14 mL

The crude, gummy compound 13 is dissolved in 14 ml of the solvent mixture by heating to 90 ° C. The solution is allowed to cool and 0.14 grams of compound 4 (> 99.5% ee) is seeded at 10 ° C intervals. At 55 ° C, the fourth seed portion no longer dissolves and forms a white, crystalline mass on further slow cooling to room temperature. The reaction mixture is filtered, washed with 3 mL of a methylcyclohexane / EtOAc solvent mixture and dried in a vacuum oven with a N ₂ flow to give 0.95 g of a white solid. The enantiomeric purity assay on a Chiracell AS column shows 93% ee.

Example XII. Preparation of trans-3- (4-pyridyl) acrylic acid.

To a solution of 4-pyridine carboxaldehyde (36.7 mL, 0.384 mol) and malonic acid (40 g, 0.384 mol) in 31 mL of pyridine was added piperidine (0.12 mL) and the mixture was heated to 100 ° C. Note: a large volume of CO ₂ is released. After 0.5 hours the reaction is cooled to room temperature (TP) and the solution solidifies. The solid is triturated with 240 ml of water, filtered and rinsed with 2 x 50 ml aliquots of water. The solid is dried overnight at 42 ° C under vacuum (10 mm Hg) giving 37.1 g of a white solid; mp 295-297 ° C.

Example XIII. Preparation of N- (2 (R) -hydroxy-1 (S) -indanyl) -trans-3- (4-pyridyl) acrylamide.

Triethylamine (10.29 ml, 0.0738 mol) is added to a suspension of trans-3- (4-pyridyl) acrylic acid (10.0 g, 0.067 mol) in 500 mL of THF and the solution is cooled to 0 ° C. Trimethylacetyl chloride (8.68 ml, 0.0704 mol) was added and the mixture was stirred for 0.5 hour. 2 (R) -hydroxy-1 (S) -indane (10.0 g, 0.067 mol), dissolved in 260 mL, is added via a cannula.

179 039

THF. After 2 hours, the reaction mixture is warmed to RT and stirred an additional 15 hours. The solvent is removed in vacuo and the resulting solid is triturated with cold ethyl acetate (150 ml) then filtered. The solid is dried overnight in vacuo (0.5 mg Hg) to give 18.5 g of a white solid; mp 205-207 ° C.

Example XIV. Preparation of N- (1,2-N, O-isopropylidene-2 (R) -hydroxy-1 (S) indanyl) -trans-3 - (4-pyridyl) acrylamide.

Dimethoxypropane (49. 0 mL, 0.402 mol) followed by (±) camphorsulfonic acid (46.8 g, 0.201 mol). After 20 minutes the reaction becomes homogeneous. The mixture was stirred for 3 hours and washed with saturated NaHCO ₃ (2 x 150 ml). The aqueous layer was extracted with methylene chloride (3 x 200 mL) and the combined organic layers were dried over MgSO ₄ , filtered, and concentrated to an oil. Purification by flash chromatography (100 x 150 mm silica gel column; elution gradient 1:30:69, 2:30:68, 3:30:67, 5:30:65 MeOH: CHCl ₃ saturated NH ₃ : CH ₂ Cl ₂ ) gives 16.0 g of white foam. (Rf = 0.46 at 5:30:65 MeOH: CHCl ₃ saturated with NH ₃ : CH ₂ Cl ₂ ).

Example XV. Preparation of N- (1,2-N, O-isopropylidene-2 (R) -hydroxy-1 (S) -indanyl) -3- (4-pyridyl) propylamide.

For N- (1,2-N, O-isopropylidene-2 (R) -hydroxy-1 (S) -indanyl) -trans-3- (4-pyridyl) acrylamide (16.0 g, 0.0499 mol) dissolved in methanol (200 ml) and THF (200 ml), 14.0 g of Pd (OH) 2 on carbon (20% by weight) are added. The flask was then charged with H ₂ and stirred for 9 hours. Ar is then bubbled through the slurry, filtered through a celite pad and rinsed with ethanol (100 mL). The solvent is removed in vacuo and the product purified by flash chromatography (silica gel column 100 x 150 mm; elution gradient 1:30:69, 2:30:68, 3:30:67, 5:30:65 MeOH: CHCl ₃ saturated NH ₃ : CH ₂ Cl ₂ ) yields 13.8 g of a white foam. (Rf = 0.5 at 5:30:65 MeOH: CHCl ₃ saturated with NH ₃ : CH ₂ Cl ₂ ).

Example XVI. Preparation of N-2 (R) -hydroxy-1 (S) -indanyl) -trans-3- (3-pyridyl) acrylamide.

179 039

The title compound is prepared using a substantially identical procedure to the preparation of N- (2 (R) hydroxy-1 (S) -indanyl) -trans-3- (4-pyridyl) acrylamide, but substituting the appropriate starting materials.

Physical data: m.p. 119-120 ° C;

Analysis calculated for C17H16N2O2 0.65 H2O:

Calculated: C 69.92; H 5.97; N9.59.

Found: C 69.94; H 5.74; N 9.84.

Example XVII. Preparation of N- (1,2-N, O-isopropylidene-2 (R) -hydroxy-1 (S) indanyl) -trans-3- (3-pyridyl) acrylamide.

Using essentially the same procedure as for the preparation of N- (1,2-N, Oisopropylidene-2 (R) -hydroxy-1 (S) -indanyl) -trans-3 - (4-pyridyl) acrylamide, but substituting the appropriate starting materials , the title compound is obtained.

Physical data: m.p. 134-136 ° C;

Analysis calculated for C20H20N2O2 0.25 H2O:

Calculated: C 73.94; H 6.36; N 8.62.

Found: C 73.95; H6.18; N 8.70.

Example XVIII. Preparation of N- (1,2-N, O-isopropylidene-2 (R) -hydroxy-1 (S) indanyl) -3 - (3-pyridyl) propylamide.

Using a substantially identical procedure as for the preparation of N- (1,2-N, Oisopropylidene-2 (R) -hydroxy-1 (S) -indanyl) -3- (4-pyridyl) propylamide but substituting the appropriate starting materials, the title compound is obtained.

While the specification set forth herein illustrates the principles of the present invention, with examples serving the purpose of illustration, it will be understood that the practice of the invention covers all common variations, adaptations, and modifications as defined within the scope of the following claims and equivalents.

Publishing Department of the Polish Patent Office. Circulation of 70 copies. Price PLN 4.00.

Claims (18)

Patent claims 1. A method of producing intermediates for HIV protease inhibitors of Formula I wherein: chiral center a has the configuration S; r is equal to 1; R ¹ and R ² are linked together to form a cyclic structure selected from: R ³ is selected from a phenyl group and groups of formulas: R ⁴ is a t-butyl group. 179,039 wherein the compound of formula IV is reacted: in which the chiral center a has the configuration S; and r and R are as defined above for formula I, with an amine of formula V: wherein R ¹ , R ² and R ⁴ are as defined above for formula I, in the presence of the solvent, at a temperature from ambient temperature to the boiling point of the solvent. 2. The method according to p. The process of claim 1, characterized in that the reaction is carried out in a solvent selected from C1.3 alcohols. 3. The method according to p. The process of claim 2, wherein the reaction is carried out in methanol. 4. The method according to p. The process of claim 1, wherein the reaction is carried out in isopropanol at a temperature of 83 ° C to 85 ° C. 5. The method according to p. The process of claim 1, wherein the compound of formula IV is used, prepared by the reaction of an amide of formula III: wherein the chiral center a has the configuration S; ar and R ³ are as defined above, in the presence of a strong base at low temperature, with: a) a compound of formula II: 179 039 wherein the chiral center a has the S configuration and X is hydrogen, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl or 3-nitrobenzenesulfonyl, or with: b) epichlorohydrin of the formula: 6. The method according to p. The process of claim 5, wherein X is p-toluenesulfonyl. 7. The method according to p. 2. The process of claim 1, wherein in the compounds of formula IR ³ is a phenyl group and R ¹ and R ² together form the structure of the formula: 8. Process for the preparation of intermediates for HIV protease inhibitors of formula IV IV in which: chiral center a has the configuration S; r is equal to 1; R ³ is selected from a phenyl group and groups of the formulas: characterized by reacting an amide of formula III: wherein r and R ³ are as defined above, in the presence of a strong base at low temperature, optionally in the presence of a solvent, with: 179 039 a) a compound of formula II: οχ π where the chiral center a has the S configuration and X is hydrogen, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl or 3-nitrobenzenesulfonyl, or with: b) epichlorohydrin of the formula: Cl, 9. The method according to p. The process of claim 8, wherein a strong base is selected from the group consisting of the following: LiN [(CH3) 3Si] 2, KN [(CH3) ₃ Si] 2, NaN [(CH3) 3Si] 2, n-butyl lithium, s -butyllithium, t-butyllithium, potassium t-butoxide, lithium diisopropylamide, lithium isopropylcyclohexylamide, lithium pyrrolidide, lithium tetramethylpiperidide, phenyl lithium, isopropylmagnesium chloride and isobutylmagnesium chloride. 10. The method according to p. 9. The process of claim 9, wherein the reaction temperature is from -82 ° C to 0 ° C. 11. The method according to p. The process of claim 10, wherein the reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and t-butyl methyl ether, or a mixture thereof. 12. The method according to p. The process of claim 11, wherein the strong base is selected from the group consisting of n-butyllithium, s-butyllithium, LiN [(CH3) 3Si] 2, and lithium diisopropylamide. 13. The method according to p. The process of claim 12, wherein the metallation reaction of amide III is carried out at a temperature of -82 ° C to -40 ° C, and the reaction of the metallated derivative III with the compound of formula II is carried out at a temperature of -50 ° C to -10 ° C. 14. The method according to p. The process of claim 13, wherein the solvent is tetrahydrofuran. 15. The method according to p. 14. The process of claim 14, wherein the strong base is selected from the group consisting of n-butyllithium and LiN [(CH3) 3Si] 2. 16. The method according to p. The method of claim 15, wherein the metallation reaction of amide III is carried out at a temperature of -50 ° C to -45 ° C, and the reaction of the metallated derivative III with the compound of formula II is carried out at a temperature of -30 ° C to -20 ° C. 17. The method according to p. The process of claim 16, wherein R ³ in the compounds of formula IV is phenyl. 18. Compound of formula * * * 179 039